Cladribine, which is an acid-labile drug, has the chemical structure as set forth below:
It is also known as 2-chloro-2′-deoxyadenosine or 2-CdA.
Cladribine is an antimetabolite which has use in the treatment of lymphoproliferative disorders. It has been used to treat experimental leukemias such as L1210 and clinically for hairy cell leukemia and chronic lymphocytic leukemia as well as Waldenstrom's macroglobulinaemia. It has also been used as an immunosuppressive agent and as a modality for the treatment of a variety of autoimmune conditions including rheumatoid arthritis, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) and multiple sclerosis (see e.g., J. Liliemark, Clin. Pharmacokinet, 32(2): 120-131, 1997). It has also been investigated, either experimentally or clinically in, for example, lymphomas, Langerhan's cell histiocytosis, lupus erythematosus, chronic plaque psoriasis, Sezary syndrome, Bing-Neel syndrome, recurrent glioma, and solid tumors.
Oral delivery of drugs is often preferred to parenteral delivery for a variety of reasons, foremost patient compliance, or for cost or therapeutic considerations. Patient compliance is enhanced insofar as oral dosage forms alleviate repeated health care provider visits, or the discomfort of injections or prolonged infusion times associated with some active drugs. At a time of escalating health care costs, the reduced costs associated with oral or transmucosal administration versus parenteral administration costs gain importance. The cost of parenteral administration is much higher due to the requirement that a health care professional administer the cladribine in the health care provider setting, which also includes all attendant costs associated with such administration. Furthermore, in certain instances, therapeutic considerations such as the need for a slow release of cladribine over a prolonged period of time may be practically met only by oral or transmucosal delivery.
However, to date the oral and transmucosal delivery of cladribine has been plagued by low bioavailability (see, e.g., J. Liliemark et al., J. Clin. Oncol., 10(10): 1514-1518, 1992), and suboptimal interpatient variation (see, e.g., J. Liliemark, Clin. Pharmacokinet, 32 (2): 120-131, 1997). See also, A. Tarasuik, et al. reporting poor absorption and pH dependent lability (Arch. Immunal. et Therapiae Exper., 42: 13-15, 1994).
Cyclodextrins are cyclic oligosaccharides composed of cyclic α-(1→4) linked D-glucopyranose units. Cyclodextrins with six to eight units have been named α-, β- and γ-cyclodextrin, respectively. The number of units determines the size of the cone-shaped cavity which characterizes cyclodextrins and into which drugs may include to form stable complexes. A number of derivatives of α-, β- and γ-cyclodextrin are known in which one or more hydroxyl groups is/are replaced with ether groups or other radicals. These compounds are thus known complexing agents and have been previously used in the pharmaceutical field to form inclusion complexes with water-insoluble drugs and to thus solubilize them in aqueous media.
Recently, Schultz et al., in U.S. Pat. No. 6,194,395 B1, have described complexing and solubilizing cladribine with cyclodextrin. The Schultz et al. patent primarily addresses the problems inherent in previously described aqueous formulations of cladribine, particularly for subcutaneous and intramuscular injection. Schultz et al. have found that cladribine is not only significantly more soluble in aqueous media when formulated with cyclodextrin, but also is more stable against acid-catalyzed hydrolysis when combined with cyclodextrin. The latter finding is taught to be of particular benefit in the formulation of solid oral dosage forms, where the compound would normally undergo hydrolysis in the acid pH of the stomach contents. Schultz et al. do not appear to have described any actual work in connection with solid oral dosage forms. In fact, they describe only one method of preparing the solid dosage form, which is a melt extrusion process, in which the cladribine and cyclodextrin are mixed with other optional additives and then heated until melting occurs. Furthermore, the broad dosage ranges of 1 mg to 15 mg of cladribine and 100 mg to 500 mg of cyclodextrin listed in the patent suggest no criticality to the particular amount of cyclodextrin to be present with a given amount of cladribine in a solid oral dosage form. Indeed, these dosage ranges include many combinations which may be suitable as mixtures but not for complex formation. For example, a ratio of 1 mg of cladribine to 500 mg of cyclodextrin contains too much cyclodextrin, so that the drug would not readily leave the complex and achieve its therapeutic function. On the other hand, 15 mg of cladribine and only 100 mg of cyclodextrin would not be enough to complex that amount of cladribine.
The Schultz et al. patent does suggest improving the stability of cladribine in oral dosage forms by combining/complexing it with cyclodextrin, but does not suggest improving the drug's oral bioavailability by such means; in fact, the patent does not describe or suggest a method for enhancing or maximizing the bioavailability of cladribine from a solid oral dosage form of cladribine and cyclodextrin, or a composition specially designed to do so. Further, Schultz et al. do not suggest cladribine/cyclodextrin combinations for transmucosal administration, that is, in a form intended for administration through the mucosa lining the nasal, oral, vaginal or rectal cavities rather than via the orogastric route, much less enhancing the bioavailability of the drug when administered via such a dosage form.
Many workers have studied the solubility of specific drugs in water containing various concentrations of selected cyclodextrins in order to demonstrate that increasing concentrations of cyclodextrins increase the solubility of the drugs at selected temperatures and pH levels, as for example reported in the Schultz et al., patent. Phase solubility studies have also been performed by various workers in order to elucidate the nature of the complex formation, for example, whether the cyclodextrin and drug form a 1:1 complex or a 1:2 complex; see, for example, Harada et al. U.S. Pat. No. 4,497,803, relating to inclusion complexes of lankacidin-group antibiotics with cyclodextrin, and Shinoda at al. U.S. Pat. No. 4,478,995, relating to a complex of an acid addition salt of (2′-benzyloxycarbonyl)phenyl trans-4-guanidinomethylcyclohexanecarboxylate with a cyclodextrin.
It has been a common practice in the pharmaceutical arts to use a surplus of cyclodextrin in solid dosage forms in which the cyclodextrin is used to improve drug solubilization, unless the solubility is such that excess cyclodextrin would result in too large a dosage form. Conventional wisdom would dictate that for a solid oral dosage form, especially of an acid-labile drug such as cladribine, excess cyclodextrin would be expected to protect the drug in the acid environment of the stomach and, ideally, deliver it through the gut wall/gastric mucosa still protected as a complex with the cyclodextrin. In the bloodstream, away from the deleterious influence of stomach acid, the drug would then be expected to dissociate from the complex and perform its therapeutic function.
While Schultz et al. teach that a cladribine-cyclodextrin complex improves the water solubility and acid stability of cladribine, the art does not suggest how to maximize or enhance the benefits of the complexation in terms of bioavailability and interpatient variation when the complex is to be administered in a solid oral dosage form or a transmucosal dosage form.